Short erythropoietin-derived peptide enhances memory, improves long-term potentiation, and counteracts amyloid beta–induced pathology

Dmytriyeva, Oksana; Belmeguenaï, Amor; Bezin, Laurent; Soud, Katia; Gøtzsche, Casper René; Pankratova, Stanislava

doi:10.1016/j.neurobiolaging.2019.05.003

Cited by 20 publications

(26 citation statements)

References 110 publications

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“…A, Induction of LTP by theta burst pairing protocol stimulation (TBP; indicated by arrow) in hippocampal slices from healthy rats (Ctrl) and from rats subjected to pilocarpine-induced SE. 72 Slices were perfused either with saline (Ctrl or SE) or GAO-3-02 (SE GAO). B, C, LTP induction in hippocampal slices from rats subjected to pilocarpine-induced SE and injected (intraperitoneally [i.p.])…”

Section: Planned Studiesmentioning

confidence: 99%

“…GAO‐3‐02 rescued and prevented long‐term potentiation (LTP) deficit in hippocampal CA1 pyramidal neurons following pilocarpine‐induced status epilepticus (SE). A, Induction of LTP by theta burst pairing protocol stimulation (TBP; indicated by arrow) in hippocampal slices from healthy rats (Ctrl) and from rats subjected to pilocarpine‐induced SE 72 . Slices were perfused either with saline (Ctrl or SE) or GAO‐3‐02 (SE GAO).…”

Section: Gao‐3‐02mentioning

confidence: 99%

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Progress report on new antiepileptic drugs: A summary of the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV). I. Drugs in preclinical and early clinical development

Bialer

Johannessen

Koepp³

et al. 2020

Epilepsia

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Since 1992, the Eilat Conferences have provided a forum for all stakeholders in the epilepsy community to appraise the latest data on new antiepileptic drugs and emergency seizure treatments, including, in recent years, updates on progress with the development of novel monitoring and therapeutic devices. Because of the COVID-19 pandemic, the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV) was held as a fully virtual conference on July 27-30, 2020 for the sessions on drugs and on August 3, 2020 for the sessions on devices, and was attended during the 5 days by >500 participants from 63 countries. This progress report summarizes key preclinical and initial (phase 1) clinical data on eight investigational treatments that are currently in early development, including 2-deoxy-D-glucose, GAO-3-02, JNJ-40411813, NBI-921352, NTX-001, sec-butylpropylacetamide, XEN1101, and XEN496. This report provides an overview of current scenarios in the area of treatment discovery and development. The information presented illustrates a variety of innovative strategies, including exploration of compounds with | 2341 BIALER Et AL. 1 | INTRODUCTION Despite the introduction of >20 second-generation antiepileptic drugs (AEDs) during the past 3 decades, including 10 new AEDs between 2008 and 2020, >30% of people with epilepsy do not attain seizure control with currently available medications, and for some epilepsy syndromes seizure outcome is even worse. 1 Hence, there is still an urgent need for newer, more effective treatments for epilepsy. Efforts to develop treatments with improved tolerability and safety are also warranted. Since 1992, the Eilat Conferences have provided a forum for stakeholders involved in clinical care, basic and clinical research, and regulatory agencies to meet on a biennial basis and discuss the latest advances in the discovery and development of new epilepsy treatments. Since 2016, sessions dedicated to discussion of novel therapeutic devices as well as devices for seizure monitoring were added to the Conferences' program. Because of the disruption caused by the COVID-19 pandemic, the 2020 Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV) was held virtually on July 27-30, 2020 for the sessions on drugs, and on August 3, 2020 for the sessions on devices. A total of 534 participants from 63 countries attended the conference, with about 75% of attendees being health care professionals/academic researchers and 25% being professionals working in the pharmaceutical industry. The virtual format did not prevent lively interactions among participants, and presenters were able to address in real time the many questions raised by the audience. Nevertheless, the face-to-face discussions, the social interaction, and the networking opportunities made possible by the physical presence of participants were surely missed. Accordingly, the Organizing Committee is confident that the next conference scheduled for 2022 will revert to the traditional format and unique boutique a...

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Section: Planned Studiesmentioning

confidence: 99%

Section: Gao‐3‐02mentioning

confidence: 99%

Progress report on new antiepileptic drugs: A summary of the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV). I. Drugs in preclinical and early clinical development

Bialer

Johannessen

Koepp³

et al. 2020

Epilepsia

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“…Non-erythropoietic neuroprotective peptides designed using EPO crystal structure information have been shown to produce cognitive effects when administered at high doses (5 mg/kg) despite half-life of only 2 min. 19,20 However, unlike EPO, antidepressant effects were not observed in clinical testing. 21 Additional work is necessary to understand the differences in receptor binding and behavioral effects produced by short peptides and full-length proteins.…”

Section: Dovepressmentioning

confidence: 99%

<p>Design and Development of a Behaviorally Active Recombinant Neurotrophic Factor</p>

Pekas¹,

Petersen²,

Sathyanesan³

et al. 2020

DDDT

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Introduction: Carbamoylated erythropoietin (CEPO) is a chemically engineered, nonhematopoietic derivative of erythropoietin (EPO) that retains its antidepressant and procognitive effects, which are attributed to the increased expression of neurotrophic factors like brain derived neurotrophic factor (BDNF), in the central nervous system. However, the chemical modification process which produces CEPO from erythropoietin (EPO) requires pure EPO as raw material, is challenging to scale-up and can also cause batch-to-batch variability. To address these key limitations while retaining its behavioral effects, we designed, expressed and analyzed a triple, glutamine, substitution recombinant mimetic of CEPO, named QPO. Methods and Materials: We employ a combination of computational structural biology, molecular, cellular and behavioral assays to design, produce, purify and test QPO. Results: QPO was shown to be a nonhematopoietic polypeptide with significant antidepressant-like and pro-cognitive behavioral effects in rodent assays while significantly upregulating BDNF expression in-vitro and in-vivo. The in-silico binding affinity analysis of QPO bound to the EPOR/EPOR homodimer receptor shows significantly decreased binding to Active Site 2, but not Active Site 1, of EPOR. Discussion: The results of the behavioral and gene expression analysis imply that QPO is a successful CEPO mimetic protein and potentially acts via a similar neurotrophic mechanism, making it a drug development target for psychiatric disorders. The decreased binding to Active Site 2 could imply that this active site is not involved in neuroactive signaling and could allow the development of a functional innate repair receptor (IRR) model. Substituting the three glutamine substitution residues with arginine (RPO) resulted in the loss of behavioral activity, indicating the importance of glutamine residues at those positions.

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“…При этом продолжительное введение NL100 не вызывает увеличение гемопоэза, в отличие от Эпо. В экспериментальных исследованиях выявлен эффект улучшения функции кратковременной памяти как у здоровых крыс, так и после центрального введения β-амилоидного пептида, а также улучшение пространственной памяти [64].…”

Section: пептидные производные эритропоэтина обладающие тканезащитныunclassified

Pathogenic substantiation of application of erythropoietin modified forms and peptide analogues as cytotprotectors

Ivanov¹,

Никифоров²,

Венгерович

et al. 2020

Pharmacy Formulas

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Provides a review of the evidence from experimental and clinical studies on the blood-forming and non-blood-forming tissue protective effects of erythropoietin. Information on its side effects (stimulation of tumor growth, autoimmune reactions, arterial hypertension, etc.), limiting the clinical use as a cytoprotector, is summarized. Well-known modifications of the erythropoietin molecule with a tissue protective effect are considered, in particular, desialylated (asialoEPO), carboxylated (CEPO) and glutaraldehyde (GEPO) cytokine analogues. The results of biomedical studies describing the tissue protective effects of these compounds, as well as possible mechanisms of their receptor action, are presented. The article discusses the main short-chain erythropoietin mimetics that reproduce individual active regions of cytokine amino acid sequence and contain from 11 to 25 amino acids: Helix B, ARA290, Eportis, Epopeptide-ab, MK-X, Epobis, NL100. The biochemical mechanisms of cytoprotective action of erythropoietin and its derivatives are considered, including binding to the heterodimeric receptor of non-blood-forming tissues and activation of intracellular signaling molecules possessing properties of apopotosis inhibitors. It was noted that the tissue protective effect of erythropoietin in vivo is observed in hemostimulating doses and is accompanied by side effects. At the same time, the use of modified forms of erythropoietin and its short-chain peptide analogues, which have a high affinity for the isoform of the erythropoietin receptor of non-blood-forming tissues and do not have hematopoietic properties, allows avoiding the development of side effects and reducing effective doses by 10-20 times.

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Short erythropoietin-derived peptide enhances memory, improves long-term potentiation, and counteracts amyloid beta–induced pathology

Cited by 20 publications

References 110 publications

Progress report on new antiepileptic drugs: A summary of the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV). I. Drugs in preclinical and early clinical development

Progress report on new antiepileptic drugs: A summary of the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV). I. Drugs in preclinical and early clinical development

<p>Design and Development of a Behaviorally Active Recombinant Neurotrophic Factor</p>

Pathogenic substantiation of application of erythropoietin modified forms and peptide analogues as cytotprotectors

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